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A case of two gastric carcinoid tumors accompanied by diffuse argyrophil-cell hyperplasia occurred in a 39-year-old woman. One of the gastric carcinoid tumors demonstrated stromal ossification. Diffuse argyrophil-cell hyperplasia accompanied by gastric carcinoid tumors has been reported previously. The significance of this association is unknown.
We present a girl with short stature, growth hormone neurosecretory dysfunction, severe hypoplastic/aplastic changes of the bones of the hands and feet with dysharmonic ossification, severely delayed bone age, microcrania, and fibular hypoplasia. Parental consanguinity suggests autosomal recessive inheritance. An additional three cases [Eiken et al., 1984: Eur J Pediatr 141: 231-235] sharing some of the radiographic manifestations of this patient have been reported. However, distinctive findings in the present case seem to outline a separate entity.
OBJECTIVE: Male mice of the DBA/1 inbred strain spontaneously develop polyarthritis and toe stiffness when they are > or =4 months old. The arthritis affects predominantly the proximal interphalangeal joints and the ankle of the hind limbs. The current study was aimed at determining the importance of T lymphocytes in this disease. METHODS: Histologic sections of hindpaws from arthritic DBA/1 mice were examined. The role of T lymphocytes was studied by using mice lacking either alpha/beta or gamma/delta T cells due to a deletion in T cell receptor beta (TCRbeta) or TCRdelta genes. RESULTS: Arthritis was associated with a massive proliferation of connective tissue (fibroblasts) in synovium and adjacent tissues. Chondroid and bone tissue outgrowth at the entheses generated periarticular osteophytes (enthesophytes) which were deposited on the unchanged margins of the preexisting bone. In some cases, the enthesophytes enlarged enough to bridge and fuse the bones by marginal ankylosis. Articular cartilage was essentially unaffected. Abnormal chondroid tissue formation was common in stiffened toes, suggesting that the same pathology may underlie both joint stiffness and arthritis. Dividing chondrocytes were commonly seen in tendons, but without correlation with arthritis or toe stiffness. Mice lacking alpha/beta or gamma/delta T cells developed arthritis at the same incidence as control littermates. CONCLUSION: The naturally occurring arthritis in male DBA/1 mice is a T cell-independent enthesopathy characterized by periarticular hyperostosis and marginal ankylosis. This suggests that the ossification leading to peripheral ankylosis of the joints in human enthesopathies, such as diffuse idiopathic skeletal hyperostosis and seronegative spondylarthropathies, is a T cell-independent process.
We examined the spatio-temporal pattern of type X collagen mRNA and its protein in the embryonic chick vertebrae undergoing ossification by in situ hybridization and immunohistochemistry. Hypertrophic chondrocytes, producing type X collagen, were developed as islands of cells in a few vertebral body segments of stage 36 embryos. These cells were increased in number at stages 37 and 38 and they expressed high levels of type X collagen mRNA and deposited its protein in the matrix. Blood vessels entered from the perichondrium at stage 37 and invaded deeply into hypertrophic cartilage at stage 38. As the vertebrae grew further at stage 40, the leading front of active hypertrophic chondrocytes with high levels of type X mRNA shifted from the midvertebral perivascular area towards intervertebral borders, while the perivascular area retained a number of inactive hypertrophic chondrocytes with low levels of type X mRNA. Type X collagen was found in large amounts throughout the matrix areas containing both active and inactive hypertrophic chondrocytes. Calcium was detected by von Kossa's technique in hypertrophic cartilage matrix in a small amount at stage 37, in parts of the matrix with type X collagen deposition in succeeding stages, and finally in almost the entire area of type X collagen deposition at stage 45. The vertebral segments of stage 45 embryos also showed a clearly reversed pattern of expression between type X collagen mRNA and types II and IX collagen mRNAs. The results demonstrate that the production of type X collagen by hypertrophic chondrocytes precedes both vascular invasion and mineralization of the matrix, suggesting that hypertrophic chondrocytes have an important role in regulating these events.
BACKGROUND: Mechanical usage effects could explain many features of endochondral ossification and related processes. Mineralization of growth plate cartilage could reduce its mechanical strains enough to make its resorption begin and to guide it in space. By removing most of its mineralized vertical septae, resorption could overload the remainder enough to increase woven bone formation on them and construct the primary spongiosa. After it finishes mineralizing, the primary spongiosa could become stiff enough to begin partial disuse in strain terms, so BMU-based remodeling would begin replacing it with lamellar bone. This would construct the secondary spongiosa. In transferring loads from the growth plate to the cortex, the central metaphyseal spongiosa becomes deloaded. This disuse would make remodeling remove it in the diaphyseal marrow space. METHODS: The slow growth of epiphyses and apophyses gives their spongiosas more time to adapt to their loads than the metaphyseal spongiosa beneath faster growing growth plates. Compared to metaphyseal trabeculae, this leads to fewer and thicker epiphyseal trabeculae that turn over more slowly and should persist for life because they carry loads for life. RESULTS: Rapid turnover of metaphyseal cortex in very young subjects could let it strain enough to form woven bone. Increased thickness and slower turnover of this cortex in older subjects could reduce its strains enough to make lamellar bone form there instead. This would compose this cortex mostly of woven bone in the very young and of lamellar bone in adults. CONCLUSIONS: This model assigns particular importance to the stiffness and strains of tissues (as distinguished from their strength and stresses), to the relative rates of some processes, and to responses of the skeleton's biologic mechanisms to a tissue's typical largest mechanical strains (as distinguished from their stresses).
A biomechanical model of endochondral ossification (Frost and Jee, 1994. Anat. Rec., 240:435-446) can help to explain: (1) some differences in fracture patterns in children and adults, (2) increased fractures during the human adolescent growth spurt, (3) localization of stress fractures and pseudofractures to cortical instead of trabecular bone, (4) increased bone mass in adult-acquired and childhood obesity, (5) subchondral bone densification and osteopenia in some arthroses, (6) why and where mammals lose spongiosa with aging, (7) why, as percents of the original bone stock, metaphyseal trabecular bone losses with aging usually exceed cortical bone losses, (8) why osteochondritis dissecans and aseptic necroses of bone localize in epiphyses instead of metaphyses, (9) some features of growth plate histology in rickets and the chondrodystrophies, (10) why spontaneous fractures in osteoporotic patients affect vertebral more than metaphyseal spongiosa, (11) why osteopenias develop in most chronic, debilitating diseases, and (12) why histomorphometric values can differ in iliac bone biopsies obtained by the "vertical" Jamshidi and "horizontal" Bordier-Meunier techniques.
A 13-year-old female sustained a rare avulsion fracture of the secondary ossification center in the superior margin of the acetabulum as the result of contraction of the reflected head of the rectus femoris muscle. Diagnosis was made from plain films and CT scans with 3D image reconstruction. The patient was treated non-operatively by bed rest with semiflexion of the hip and knee, and appropriate analgesia.
In the transformation of the cartilaginous epiphysis into bone, the first indication of change in the surfaces destined for resorption is the cleavage of aggrecan core protein by unidentified matrix metalloproteinases (MMPs) (Lee et al., this issue). In cartilage areas undergoing resorption, the cleavage leaves as superficial, 6-microm-thick band of matrix, referred to as "pre-resorptive layer." This layer harbors G1-fragments of the aggrecan core protein within a framework of collagen-rich fibrils exhibiting various stages of degeneration. Investigation of this layer in every resorption area by gelatin histozymography and TIMP-2 histochemistry demonstrates the presence of an MMP whose histozymographic activity is inhibited by such a low dose of the inhibitor CT1746 as to identify it as gelatinase A or B. Attempts at blocking the histozymographic reactions with neutralizing antibodies capable of inhibiting either gelatinase A or B reveals that only those against gelatinase B do so. Immunostaining of sections with anti-gelatinase B IgG confirms the presence of gelatinase B in every pre-resorptive layer, that is, at the blind end of excavated canals (stage I; 6-day-old rats), at sites along the walls of the forming marrow space (stage II; 7days), at sites within the walls of this space as it becomes the ossification center (stage III; 9 days) and along the wall of the maturing center (stage IV; 10-21 days). We also report the presence of collagenase-3 in precisely the same sites, possibly as active enzyme, but this remains to be proven. Because the results reveal that collagenase-3 is present beside gelatinase B in every pre-resorptive layer and, because these sites exhibit various signs of degradation including fibrillar debris, reduction in fibril number, or overt loss, we propose that gelatinase B and collagenase-3 mediate the lysis of this pre-resorptive layer-most likely through a cooperative attack leading to the disintegration of the collagen fibril framework.
The use of osmium-potassium ferrocyanide as the secondary fixative greatly improved chondrocyte preservation and stabilized the cartilage matrix proteoglycan. The proteoglycan was similar in appearance to that seen following fixation in the presence of cationic dyes. Extensive glycogen preservation was noted in these cells, occupying the area prior to and during the formation of the secondary center of ossification. The volume and organization of the glycogen within the cell cytoplasm were greater than that following buffered osmium fixation, and the cellular vacuoles within were greatly reduced. The cells forming the secondary center prior to the onset of mineralization were of greatest interest, because other studies compared them with the primary growth plate and described them as showing signs of hypertrophy as early as 5 days postnatally, as is found in the primary growth plate. Our observations indicate that glycogen is present in these cells, and cellular enlargement was not present. The cells do not resemble the hypertrophic chondrocytes of the primary growth plate, as far as cytoplasmic content is concerned, and we suggest that they may contribute to the development of the secondary center in a different fashion.
The ontogenetic sequence of cranial osteogenesis through adulthood is described in samples of newts from completely metamorphosing and partially neotenic populations. Cranial ossification proceeds in the same sequence in both samples. Seven stages of cranial development are described on the basis of conspicuous events that occur during ontogeny. These include four larval stages, metamorphs, efts, and adults. Neotenic adults have skulls that are metamorphosed completely and indistinguishable from the skulls of non-neotenic adults. Neoteny in these newts does not involve the skull and is limited to the postmetamorphic retention of some gill structures and, thus, is termed "limited neoteny." The evolution of limited neoteny in newts as a correlated response to the inhibition of land-drive behavior is discussed.
Immunohistochemical methods were employed to examine alterations in the cartilage extracellular matrix constituents associated with endochondral ossification in humans. The distributions of chondroitin 4- and 6-sulfate and keratan sulfate proteoglycan (PG) determinants, cartilage PG link protein, collagen types I and II, and fibronectin were determined in iliac crest growth-plate specimens using the avidin-biotin-horseradish peroxidase system. Collagen type II was distributed throughout the growth plate, providing a framework within which chondrocytes divided and formed clusters of differentiating (hypertrophic) cells. The septa between these clusters and their subchondral extensions into underlying bone trabeculae were rich in PG, PG link protein, and collagen type II and resembled the extracellular matrix of reserve cartilage. The territorial matrix associated with the differentiating cells within the clusters contained reduced amounts of collagen type II, PG link protein, and possibly cartilage PG. Collagen type I and fibronectin were detected within the cytoplasm of the maturing and degenerating cells, and fibronectin localized intensely to the pericellular matrix envelopes of these cells. These alterations presumably facilitate the degradation of the matrix associated with the cell clusters by invading vascular tissue, while the septa, which retain the characteristics of more typical cartilage matrix, are not degraded and firmly anchor the cartilage to the subchondral bone.
Using a rat fracture model, we investigated the effects of a decrease in serum levels of thyroid hormone on the fracture-repair process. Rats were divided into the following groups: (a) controls, (b) those treated with methimazole for the duration of the experiment, and (c) those treated with methimazole and L-thyroxine, receiving both for the same duration. Three weeks after the initiation of pharmacologic treatment, closed femoral fractures were produced. The formation of cartilage tissue in the fracture callus in all rats was not obviously different on day 7 after fracture. In the rats treated with methimazole, differentiation from proliferating to hypertrophic chondrocytes in the fracture callus was less advanced and vascular invasion was clearly inhibited on day 12. Gene expression of alkaline phosphatase and osteocalcin in the callus was significantly lower in these rats than in the controls on days 10, 12, and 14. The mechanical properties of the fracture callus were also significantly weaker in these animals than in the controls on day 21, resulting in impaired fracture repair. These results demonstrate that hypothyroidism inhibits endochondral ossification, resulting in an impaired fracture-repair process. L-thyroxine replacement in the rats treated with methimazole caused the impaired repair process to revert to normal. These results indicate that thyroid hormone is one of the critical systemic factors for fracture repair.
Fibrodysplasia ossificans progressiva (FOP) is a rare heritable genetic disorder, which is characterized pathologically by sporadic episodes of explosive growth of mesenchymal cells in skeletal muscle followed by cellular differentiation to heterotopic bone through an endochondral process. This study examined the histological origin and differentiation state of stromal cells in early FOP lesions and investigated the association between the phenotype of these FOP cells and bone formation. Interestingly, FOP lesional stromal cells were found to display characteristics of the smooth muscle (SM) cell lineage and are therefore potentially of vascular origin. These cells co-express multiple SM lineage markers along with multiple proteins associated with bone formation including the obligate osteogenic transcription factor Runx2/Cbfa-1. It is hypothesized that the stromal cells of early FOP lesions may be locally recruited vascular cells or cells of the bone marrow stroma and that these cells maintain the potential (given the correct environmental stimuli) to differentiate along an endochondral ossification pathway.
A case of severe lethal neonatal dwarfism is reported. It appears to be a new variety of short rib-polydactyly dwarfism. It is characterized by severe lack of ossification of all bones except the clavicle and the presence of cleft palate, as well as genitourinary, central nervous system and cardiovascular anomalies. Electronmicroscopy revealed accumulations of granular material in the chondrocytes.
In order to examine the involvement of leptin in the ossification of spinal ligaments (OSL), the present study examined (i) serum levels of leptin and insulin in OSL patients and controls, (ii) serum leptin levels in children of OSL females with severe obesity, (iii) the expression of leptin receptor mRNA in human spinal ligaments, and (iv) effects of leptin on cultured human ligament cells. In the OSL females, serum leptin levels were significantly higher than those of the control females, and the levels were positively correlated to the serum insulin levels, while in the control females, there was a tendency of inverse correlation. The daughters of OSL females with severe obesity also had high serum leptin levels, although they had not developed OSL. The expression of leptin receptor mRNA was confirmed in the ligaments, but leptin did not influence the alkaline phosphatase activity nor procollagen type I carboxyl-terminal peptide content of the ligament cells. These findings suggest that leptin is involved genetically and indirectly with the pathogenesis of OSL in female patients.
An understanding of trabecular formation in early skeletal development may provide insight into the problem of trabecular replacement in the aging skeleton. In an optical and scanning electron microscope study of the processes of de novo trabecular generation, the immunohistochemical distribution of collagen Types I, II and III, together with the matrix organising proteins fibronectin and tenascin, has been examined in the ossifying human femoral anlage. In the region of the developing spongiosa, the primary osseous trabeculae that arose by endochondral ossification were assembled around calcified cartilage remnants, consisting almost entirely of aggregates of mineralised microspheres. These structures were specifically recognised by antibodies raised against collagen Type II and fibronectin. In contrast, the primary osseous trabeculae that arose by subperiosteal intramembranous processes, were assembled around a framework of prominent coarse fibres that were recognised by antibodies raised against collagen Type III and tenascin. Irrespective of their origin, all the new trabeculae were similar in their general staining character for collagen Type I and fibronectin. However, throughout the developmental stages examined here endochondral trabeculae were separated from intramembranous trabeculae by a discrete boundary of compressed cells and mineralised cartilage.
Two-week-old white leghorn chicks were fed a diet containing BAPN (0.05%) for three weeks. Thirty-six hours before sacrifice, the controls and BAPN fed chicks were dosed with 35S. The zone of provisional calcification was isolated, and 35S incorporation was estimated by liquid scintillation counting. Alkaline phosphatase and Ca+2-ATPase were biochemically analyzed. Microdensitometry, to assess the level of mineralization, was done on epiphysis and the metaphysis. Morphometry was performed on the various zones of growth plate. 35S incorporation was significantly lower in the bones of BAPN treated chicks as compared to the controls. The enzymatic studies showed a significant inhibition of alkaline phosphatase and Ca+2-ATPase. The microdensitometric studies showed a smaller area of highly mineralized bone in the zones of provisional calcification of the BAPN treated chicks as compared to the controls. Morphometry showed a reduction in the width of the zone of calcification in BAPN treated chicks as compared to the controls. On the basis of the above data, it is suggested that BAPN induced inhibition of mineralization during endochondral ossification may be the result of a lower synthesis of sulfur containing GAG's, the inhibition of enzymes alkaline phosphatase and Ca+2-ATPase and the derangement of cellular zones of the growth plate. The implications of these results lie in the fact that mineralization is dependent on multifactorial control of the microenvironment of bone and cartilage.
Ossification of calvariae from day-21 rat fetuses was reinvestigated by electron microscopy using different fixation techniques (glutaraldehyde/OsO4, tannic acid, ruthenium red, K-pyroantimonate). An osteoid layer with scattered mineral deposits was found at the mineralization front. Directly beyond this layer, a sheet of one to two layers of necrotic and degenerating osteoblasts was present. Above this sheet, normal and healthy cells were seen, formed by six to eight layers of flattened cells, embedded in a collagenous matrix. The osteoblasts on the less mineralizing opposite side of the calcified calvariae and the osteocytes embedded in the calcified calvariae appeared healthy. Closer inspection of the necrotic zone revealed apatite crystals in vesicles which most probably originated from mitochondria of the degenerated cells. Large K-pyroantimonate deposits were found throughout the osteoid and the necrotic zone, whereas only small granules were scattered in the cytoplasm and at the plasma membrane of the healthy cells directly adjacent to the necrotic zone. A concept of intramembranous mineralization is outlined, according to which osteoblasts store enormous amounts of calcium, which are liberated by physiological cell death in the vicinity of the mineralizing front.